Nilotinib, sold under the brand name Tasigna marketed worldwide by

Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...

, is a medication used to treat

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...

(CML) which has the

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

. It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to

imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...

. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Common side effects may include

low platelets Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...

low white blood cells Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

, rashes, vomiting,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

, and joint pains. Other serious side effects may include

QT prolongation Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...

, sudden death,

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

, and

liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the sig ...

. It is not safe for use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

. Nilotinib is a

Bcr-Abl tyrosine kinase inhibitor Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelp ...

and works by interfering with signalling within the cancer cell. Nilotinib was approved for medical use in the United States in 2007. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

Medical uses

Nilotinib is used to treat

(Ph+)-positive chronic myelogenous leukaemia.

Adverse effects

Nilotinib has a number of adverse effects including headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain,

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...

and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as high blood pressure, various types of

arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

, and prolonged

QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...

. Nilotinib can also affect the body's

electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...

and

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

balance. Though lung-related adverse effects are rare when compared with

and

dasatinib Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that ar ...

, there is a case report of acute respiratory failure from

diffuse alveolar hemorrhage Pulmonary hemorrhage (or pulmonary haemorrhage) is an acute bleeding from the lung, from the upper respiratory tract and the trachea, and the pulmonary alveoli. When evident clinically, the condition is usually massive.black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it i ...

in the United States for possible heart complications. Contraindications include

long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...

hypokalaemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnor ...

hypomagnesaemia Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, an ...

, pregnancy, planned pregnancy, lactation and galactose/

lactose intolerance Lactose intolerance is a common condition caused by a decreased ability to digest lactose, a sugar found in dairy products. Those affected vary in the amount of lactose they can tolerate before symptoms develop. Symptoms may include abdominal pa ...

. Cautions include: * Myelosuppression * Tumour lysis syndrome * Liver impairment * History of pancreatitis * Check serum lipase periodically in order to detect pancreatitis * Total gastrectomy * Avoid pregnancy or impregnating women Dose reduction has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities.

Hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...

virus reactivation may also occur.

Interactions

Nilotinib has been reported as a substrate for OATP1B1 and OATP1B3. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. It is a substrate for

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

and hence grapefruit juice and other

inhibitors will increase its action and inducers like St. John's wort will decrease it. Patients report that pomegranates and starfruit may also interfere. Food should not be eaten two hours before or one hour afterwards because it unpredictably increases its bioavailability, approximately doubling it.

Pharmacology

Nilotinib inhibits the kinases

BCR-ABL The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

, KIT,

LCK Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...

EPHA3 EPH receptor A3 (ephrin type-A receptor 3) is a protein that in humans is encoded by the ''EPHA3'' gene. Function This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been ...

, EPHA8,

DDR1 Discoidin domain receptor family, member 1, also known as DDR1 or CD167a (cluster of differentiation 167a), is a human gene. Function Receptor tyrosine kinases (RTKs) play a key role in the communication of cells with their microenvironment. ...

, DDR2,

PDGFRB Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the ''PDGFRB'' gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies. Gene The ''PDGFRB'' gene is located on hu ...

MAPK11 Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the ''MAPK11'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...

and

ZAK Zak may refer to: People * Zak (surname), a surname of Russian origin * Żak, a Polish surname * Žák, a Czech surname * Zak (given name) Fictional characters * Zak Adama, in the '' Battlestar Galactica'' franchise * Zak Dingle, in UK TV ''Emme ...

. Structurally related to imatinib, It is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.

History

Nilotinib was developed by

. It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. It was approved for medical use by the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in October 2007, EMA in September 2009, MHRA in November 2007, and TGA in January 2008.

Research

Parkinson's disease

There is weak evidence that nilotinib may be beneficial with

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

(PD), with a small clinical trial suggesting it might halt progression and improve symptoms. However, there were significant side effects including

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

liver function test Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...

s abnormalities,

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...

s and

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...

, and the benefit in PD disappeared at follow up after drug discontinuation, raising question as to whether it was truly a disease modifying therapy. Nilotinib is currently undergoing phase II studies for treatment of Parkinson's. Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson's due to the significant media hype surrounding the small and early clinical trial. Dystonia and cognitive impairment have also been reported as side effects.

Other

Novartis announced on April 11, 2011, that it was discontinuing a phase III trial of nilotinib as the first-line treatment of

gastrointestinal stromal tumor Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior is ...

(GIST) based on the recommendation of an independent data monitoring committee. Interim results showed Tasigna is unlikely to demonstrate superiority compared to Novartis's Gleevec (imatinib)*, the current standard of care in this setting. Low dose nilotinib is also being investigated for use in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, as well as for

ALS Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most com ...

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

and

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

References

External links

* {{Portal bar , Medicine Orphan drugs Non-receptor tyrosine kinase inhibitors Imidazoles CYP2D6 inhibitors Novartis brands Trifluoromethyl compounds Benzanilides Aminopyrimidines 3-Pyridyl compounds Wikipedia medicine articles ready to translate